Rational use of mucoactive medications to treat pediatric airway disease.

Many airway diseases in children, notably bronchiolitis, cystic fibrosis (CF), non-CF bronchiectasis including primary ciliary dyskinesia, pneumonia, and severe asthma are associated with retention of airway secretions. Medications to improve secretions clearance, the mucoactive medications, are employed to treat these diseases with varying degrees of success. This manuscript reviews evidence for the use of these medications and future directions of study.

IL-33 stimulates CXCL8/IL-8 secretion in goblet cells but not normally differentiated airway cells.

BACKGROUND: IL-13, a helper T cell type 2 (Th2) cytokine, transforms cultured airway epithelial cells to goblet cells, and this is not inhibited by corticosteroids. IL-33 stimulates Th2 cytokines and is highly expressed in airways of persons with asthma. The effect of IL-33 on goblet cell differentiation and cytokine secretion has not been described. OBJECTIVE: We examined the effect of IL-33 on CXCL8/IL-8 secretion from goblet or normally differentiated human bronchial epithelial (NHBE) cells and signalling pathways associated with IL-33 activation in these cells. METHODS: Normal human bronchial epithelial cells were grown to goblet or normally differentiated ciliated cell phenotype at air-liquid interface in the presence or absence of IL-13. After 14 days, differentiated cells were exposed to IL-33 for 24 h. RESULTS: CXCL8/IL-8 secretion into the apical (air) side of the goblet cells was greater than from normally differentiated cells (P < 0.01), and IL-33 stimulated apical CXCL8/IL-8 release from goblet cells, but not from normally differentiated cells (P < 0.01). IL-33 increased ERK 1/2 phosphorylation in goblet cells (P < 0.05), and PD98059, a MAPK/ERK kinase inhibitor, attenuated IL-33-stimulated CXCL8/IL-8 secretion from goblet cells (P < 0.001). IL-13 induced ST2 mRNA (P < 0.02) and membrane-bound ST2 protein expression on the apical side surface of goblet cells compared with normally differentiated cells, and neutralization with anti-ST2R antibody attenuated IL-33-induced apical CXCL8/IL-8 secretion from goblet cells (P < 0.02). CONCLUSIONS AND CLINICAL RELEVANCE: Goblet cells secrete CXCL8/IL-8, and this is increased by IL-33 through ST2R-ERK pathway, suggesting a mechanism for enhanced airway inflammation in the asthmatic airway with goblet cell metaplasia.

IL-13-induced MUC5AC production and goblet cell differentiation is steroid resistant in human airway cells.

BACKGROUND: Glucocorticosteroids (GCS) are used to treat bronchial asthma, but are not uniformly effective, especially in severe asthma. IL-13 is a T helper type 2 cytokine implicated in the pathogenesis of asthma, and IL-13 induces mucus production and goblet cell hyperplasia in airway epithelial cells. The effect of GCS on IL-13-induced mucin production is not well characterized. OBJECTIVE: The aim of this study was to evaluate the effect of dexamethasone (Dex), a potent synthetic GCS, on IL-13-induced MUC5AC mucin expression and goblet cell proliferation in differentiated normal human bronchial epithelial cells (NHBECs). METHODS: NHBECs were cultured for 14 days at an air-liquid interface with IL-13, with or without Dex. MUC5AC protein secretion and mRNA expression was determined using ELISA and quantitative real-time PCR. IL-8 production was assayed using ELISA. Histochemical analysis was performed using H&E and periodic acid-Schiff stain, and MUC5AC immunostaining. RESULTS: Although Dex dose dependently inhibited IL-8 release induced by 5 ng/mL IL-13, Dex 0.001-1 µg/mL had no effect on IL-13 induced MUC5AC protein secretion or mRNA expression. Dex paradoxically increased MUC5AC induced by IL-13 at 0.5 and 1 ng/mL, but had no effect alone or with IL-13 at 0.1 ng/mL. Dex 0.001-1 µg/mL did not inhibit the differentiation of cells into goblet cells and MUC5AC-positive cells induced by IL-13. CONCLUSION AND CLINICAL RELEVANCE: Dex at therapeutic concentrations did not inhibit the effects of IL-13 on goblet cell differentiation, characteristic of severe asthma. Paradoxically, MUC5AC production was increased with lower dose IL-13 exposure. This may lead to airway mucus obstruction commonly seen in life-threatening asthma.

Alternative mechanisms for tiotropium.

Tiotropium is commonly used in the treatment of chronic obstructive pulmonary disease. Although largely considered to be a long-acting bronchodilator, its demonstrated efficacy in reducing the frequency of exacerbations and preliminary evidence from early studies indicating that it might slow the rate of decline in lung function suggested mechanisms of action in addition to simple bronchodilation. This hypothesis was examined in the recently published UPLIFT study and, although spirometric and other clinical benefits of tiotropium treatment extended to four years, the rate of decline in lung function did not appear to be reduced by the addition of tiotropium in this study. This article summarizes data from a variety of investigations that provide insights into possible mechanisms to account for the effects of tiotropium. The report summarizes the discussion on basic and clinical research in this field.

Effect of a single 1200 Mg dose of Mucinex® on mucociliary and cough clearance during an acute respiratory tract infection.

BACKGROUND: Observational studies suggest that orally administered guaifenesin (GGE) may thin lower respiratory tract secretions but none have examined its effects on mucociliary and cough clearance (MCC/CC) during a respiratory tract infection (RTI). The current study was a randomized, parallel-group, double-blind, placebo-controlled study in non-smoking adults who suffered from an acute upper RTI. METHODS: We assessed the effects of a single dose of Mucinex(®) 1200 mg (2 × 600 mg extended release tablets) (ER GGE) on 1) MCC/CC by assessing the rate of removal from the lung of inhaled radioactive tracer particles (Tc99m-sulfur colloid), 2) sputum dynamic rheology by stress/strain creep transformation over the linear part of the curve, 3) sessile drop interfacial tension by the deNouy ring technique, and 4) subjective symptom measures. MCC was measured during the morning (period 1) and compared to that in the afternoon 4 h later (period 2) immediately following either drug (n = 19) or placebo (n = 19). For both period 1 and 2 subjects performed 60 voluntary coughs from 60 to 90 min after inhalation of radio-labeled aerosol for a measure of CC. Sputum properties were measured from subjects who expectorated sputum during the cough period post treatment (n = 8-12 for each cohort). RESULTS: We found no effect of ER GGE on MCC or CC compared to placebo. MCC through 60 min for period 1 vs. 2 = 8.3 vs. 11.8% (placebo) and = 9.7 vs. 11.1% (drug) (NS) and CC for period 1 vs. 2 was 9.9 vs. 9.1% (placebo) and 10.8 vs. 5.6% (drug) (NS). There was no significant difference in sputum biophysical properties after administration of drug or placebo. CONCLUSIONS: There was no significant effect of a single dose of ER GGE on MCC/CC or on sputum biophysical properties compared to placebo in this population of adult patients with an acute RTI. ClinicalTrials.gov Identifier: NCT01114581.

Fluctuations in autonomic nervous activity during sleep displayed by power spectrum analysis of heart rate variability.

OBJECTIVE: The use of an efficient noninvasive method to investigate the autonomic nervous system and cardiovascular control during sleep. BACKGROUND: Beat-to-beat heart rate variability displays two main components: a low-frequency (LF) one representing sympathetic and parasympathetic influence and a high-frequency (HF) component of parasympathetic origin. Sympathovagal balance can be defined as LF/HF ratio. METHODS/DESIGN: We reviewed normal, standardly staged all-night polysomnograms from 10 healthy children aged 6 to 17 years. Recorded 256-second traces of heart rate and respiration were sampled. Power spectra of instantaneous heart rate and respiration were computed using a fast Fourier transform method. RESULTS: The study revealed a decrease in LF during sleep, with minimal values during non-REM slow-wave sleep and elevated levels similar to those of wakefulness during REM. HF increased with sleep onset, reaching maximal values during slow-wave sleep, and behaved as a mirror image of LF. LF/HF ratio displayed changes similar to those in LF. CONCLUSION: The sympathetic predominance that characterizes wakefulness decreases during non-REM sleep, is minimal in slow-wave sleep, and surges toward mean awake levels during REM sleep. The autonomic balance is shifted toward parasympathetic predominance during slow-wave sleep. This noninvasive method used to outline autonomic activity achieves results that are in complete agreement with those obtained with direct invasive tools.

Use of anticholinergic bronchodilation in children.

Ipratropium bromide is a quaternary ammonium anticholinergic bronchodilator with minimal systemic absorption across the blood-airway barrier. Ipratropium bromide has become primary therapy for the treatment of adults with chronic bronchitis, but its use in children has been limited. Ipratropium bromide can be safely used in the management of acute bronchiolitis, recognizing that most infants do not appear to respond to any bronchodilator medication. When used with a beta-agonist bronchodilator for the therapy of acute childhood asthma, ipratropium bromide appears to provide bronchodilation beyond that achieved by either agent used alone. There are insufficient published data to determine the appropriate use if ipratropium bromide in infants with bronchopulmonary dysplasia, although many of those symptomatic after the age of 6 months seem to benefit from either ipratropium bromide or beta-agonists. As ipratropium bromide has no intrinsic anti-inflammatory properties, its role in the chronic therapy of asthma and related disorders is still unclear.

Macrolide antibiotics as biological response modifiers.

Erythromycin was first isolated in the 1950s from a Philippine soil sample, and the derivatives of erythromycin A, called the macrolide antibiotics, have been used as effective antibacterial agents ever since. It has long been suspected that the 14-membered macrolides have immunomodulatory activity as demonstrated by their early use as adjunctive therapy for asthma and their astounding effectiveness for the therapy of diffuse panbronchiolitis. It is now clear, that the macrolides and their cousins, the 15-membered azalides, and perhaps the ketolides, have a broad range of biological response modifying effects on inflammation, tumor cells, airway secretions and host defenses. This review highlights some exciting new data, as well as controversies related to understanding the mechanism of action for these diverse effects.

An in vitro comparison of the mucoactive properties of guaifenesin, iodinated glycerol, surfactant, and albuterol.

STUDY OBJECTIVE: The mechanism of action of potential mucoactive agents could relate to effects on the mucociliary apparatus or to direct effects on the secretions. The purpose of this study was to determine the in vitro effects of several agents on the properties of mucus simulants and sputum collected from 30 adults with stable chronic bronchitis. DESIGN: Sputum or simulants were analyzed untreated and after the addition of the test agent at 1:5 volume to volume ratio for a contact period of 60 s. The concentrations of the agents were as follows: guaifenesin, 20 mg/mL; iodinated glycerol, 3 mg/mL; surfactant (Exosurf; Glaxo Wellcome; Research Triangle Park, NC) containing 13.5 mg of phospholipid per milliliter; albuterol, 5 mg/mL; and amphibian Ringer's solution (ARS) as a control. Dynamic viscoelasticity and surface mechanical impedance were measured in a magnetic microrheometer. Cohesiveness was measured using a filancemeter. The wettability of a hydrophilic surface was measured using an image processing system. The mucociliary transportability of sputum was timed on the frog palate, and cough transportability (CTR) was measured in a cough machine. RESULTS: When compared to sputum that had no test agent or ARS added, all agents reduced sputum elasticity G', with surfactant, albuterol, and guaifenesin significant at p < 0.001. As well, guaifenesin (p = 0.006), albuterol (p = 0.003), and surfactant (p = 0.02) decreased surface mechanical impedance (frictional adhesiveness) compared to untreated sputum. However, there were no significant changes in wettability, hydration, cohesiveness, or CTR with any agent, and there were no significant changes in the properties of sputum or simulants treated with test agents when compared to those treated with ARS. Guaifenesin irreversibly disrupted mucociliary transport when applied directly to the frog palate. CONCLUSIONS: These agents appear to have a minimal direct action on sputum in vitro, suggesting that at the concentrations studied, these agents do not have a significant beneficial effect on either the mucociliary transportability or CTR of chronic bronchitis sputum. However, there could be an effect of some of these agents after oral administration, especially if there is a secondary effect of the agent on an effector cell.

Pulmonary function, nutrition, and self-concept in cystic fibrosis summer campers.

Children with cystic fibrosis (CF) often attend special summer camps. We postulated that beyond the simple fun of camp, attendance at camp might improve the clinical status and self-image of the campers. We therefore studied lung function, nutrition, and self-image in 45 children between the ages 6 and 12 years after a two-week CF summer camp. Although there was a 10 percent fall in respiratory rate during camp, spirometry did not change significantly. There were, however, significant gains in weight, skin fold thickness, and midarm circumference after two weeks at camp, and these increases were positively correlated with the number of pancreatic enzymes taken daily by the child. The Primary Self-Concept Inventory test was completed by each camper on the first and last days of camp. Although there was a trend toward increasing self-concept during camp, this did not reach statistical significance. Two weeks' attendance at summer camp appears to be associated with improved nutrition in children with CF. This may be due to increased emphasis on weight gain and appropriate use of pancreatic enzymes or to other factors, like avoidance of tobacco smoke exposure, that are unique to the summer camp setting.

Mucus rheology and transport in neonatal respiratory distress syndrome and the effect of surfactant therapy.

BACKGROUND: Neonatal respiratory distress syndrome (RDS) is caused by a deficiency of pulmonary surfactant. Alveolar collapse and obstruction of conducting airways leads to mismatch of ventilation and perfusion and profound hypoxemia. We postulated that surfactant deficiency could alter the properties of respiratory mucus in such a way that it would be poorly cleared from airways and promote airway luminal obstruction and that these changes might be reversed by the exogenous administration of a synthetic surfactant preparation. METHODS: Respiratory mucus coating an endotracheal tube (ETT) or suction catheter was collected from 14 neonates (gestational age, 24 to 36 weeks; birth weight, 600 to 2,400 g) with RDS who required tracheal intubation and ventilation. Eight of these neonates received 5 ml/kg of an intratracheal artificial surfactant preparation (Exosurf), given between 2 and 10 h of age and six neonates received 5 ml/kg of air. Mucus viscoelasticity, hydration (percentage of solid composition of mucus), and mucociliary clearability (NFPTR) were measured for each specimen. RESULTS: The total volume of mucus collected from the surfactant-treated and control infants was similar, but mucus hydration was significantly less in babies with RDS who did not receive Exosurf (percentage of solid composition of mucus 18.7 vs 11.4; p = 0.013). Ciliary transportability was also less in the untreated babies (NFPTR 0.39 vs 0.86; p = 0.018) and this mucus was more rigid (increased viscoelasticity: log G* 1 rad/s 2.28 vs 1.50; p = 0.0001). CONCLUSIONS: These data suggest that airway obstruction in RDS may be due, in part, to abnormal mucus properties and impaired ciliary transport. Surfactant therapy appears to improve mucus clearability. Exogenously administered surfactant may also be beneficial for the treatment of other selected respiratory conditions associated with impaired mucus clearance.

Iodinated glycerol has no effect on pulmonary function, symptom score, or sputum properties in patients with stable chronic bronchitis.

STUDY OBJECTIVE: It has been reported that therapy with iodinated glycerol (IG) can improve the quality of life for patients with chronic bronchitis. The purpose of this study was to determine the effects of IG therapy on the quality of life, pulmonary function, and on the properties of sputum collected from adults with stable chronic bronchitis. DESIGN: Thirty-two week, double-blind, randomized, placebo-controlled cross-over study. SETTING: A university outpatient pulmonary clinic. PARTICIPANTS: Twenty-six adults with stable chronic bronchitis completed the study; 28 completed the first treatment arm. INTERVENTIONS: Sixteen weeks each of placebo or IG 60 mg qid. MEASUREMENTS: First, pulmonary function by spirometry and plethysmography. Second, symptom score measured using a questionnaire. Third, sputum bulk and surface rheology, spinnability, mucociliary transportability and cough transportability. RESULTS: There were no significant changes in pulmonary function, clinical scores, or sputum properties related to therapy with IG. There was a significant improvement in the Global Petty score after both IG (p = 0.01) and placebo (p < 0.01) when compared with baseline, but there was no difference between treatment periods. There was a positive correlation between changes in the Global score during therapy and changes in sputum spinnability (p < 0.01, r = 0.38). CONCLUSIONS: This study clearly demonstrates that in chronic bronchitis, 16 weeks of therapy with IG does not produce any appreciable effect on pulmonary function, well being, or on sputum viscoelasticity or clearability.

Perfluorooctyl bromide (perflubron) stimulates mucin secretion in the ferret trachea.

OBJECTIVES: Partial liquid ventilation with perfluorooctyl bromide (perflubron) has been shown to be safe and effective in animal models with respiratory failure. However, airway mucus accumulation has been reported to be a problem in human trials. We hypothesized that this might be because perflubron directly affects mucociliary clearance or stimulates mucus secretion. METHODS AND RESULTS: We first measured the mucociliary transportability of secretions on the mucus-depleted frog palate exposed to perflubron and demonstrated that the ciliated epithelium remained intact with preservation of mucociliary transport. We then measured mucin and lysozyme secretion from isolated ferret tracheal segments to evaluate the secretagogue potential of perflubron. There was an 86% increase in mucin secretion with perflubron incubation at 40 min (n = 19; p < 0.01) and a 52% increase after 4 h of exposure followed by evaporation of perflubron (n = 19; p < 0.01). There was no significant difference in lysozyme secretion at any time between perflubron-exposed or buffer-exposed tissue (n = 4). The secretagogue effect was completely blocked by nordihydroguaiaretic acid, an inhibitor of arachidonic acid (AA) metabolism. CONCLUSION: These data suggest that although perflubron does not seem to be harmful to the airway, it induces mucus secretion in a noninflamed airway, and that this can be modulated by inhibitors of AA metabolism.

General anesthesia does not alter the viscoelastic or transport properties of human respiratory mucus.

Observations that mucus transport rates (MTR) are depressed in anesthetized animals and humans have led to speculation that general anesthesia depresses ciliary activity or adversely alters the physical properties of the respiratory mucus (RM). We investigated the possibility that anesthesia changes the physical properties of RM in such a way as to depress ciliary transport. We collected 33 samples of RM from the endotracheal tubes (ETTs) of 25 people aged 1 to 79 years undergoing elective surgery who had no clinical evidence of lung disease. We measured the rigidity, viscoelasticity, spinnability, and the percentage of solid composition of these specimens as well as the transport of the collected RM across the mucus-depleted frog palate. These physical properties were not significantly different from RM collected from awake volunteers using the bronchoscopy brush collection technique. Differences in spinnability, transportability, and solid content of paired mucus samples from the inside and outside of the ETTs are suggestive of altered RM hydration, but this requires further study. The decrease in MTR during general anesthesia is probably due to mechanisms other than alterations in the physical properties of mucus.

Ultrasonic nebulization of albuterol is no more effective than jet nebulization for the treatment of acute asthma in children.

STUDY OBJECTIVE: Nebulizer systems used to generate therapeutic aerosols vary in their ability to deliver medication to the airway. In a recent study in 17 adults with stable asthma, albuterol given using an ultrasonic nebulizer (UN) appeared to produce greater bronchodilatation than the same dose of albuterol given by a jet nebulizer (JN). The purpose of this study was to determine if the UN used in that study would produce a better bronchodilator response in children with acute asthma than the JN system that has been in use at Cardinal Glennon Children's Hospital. DESIGN: Randomized, prospective, unblinded study. SETTING: An urban university children's hospital emergency department. PARTICIPANTS: One hundred thirteen children, aged 7 to 16 years, who presented for treatment of acute moderately severe asthma completed this study. INTERVENTIONS: After randomization and exclusion of dropouts, 46 children received albuterol by UN and 67 were treated by JN. MEASUREMENTS: Pulmonary function tests (PFTs) by spirometry, pulse oximetry, and symptom score at baseline and at 15 and 30 min following a single prescribed treatment. RESULTS: PFT on entry to the study was the same in both groups (FEV1; p>0.97). The change in FEV1 after therapy (UN+0.22 L vs JN+0.37 L) was significant (p<0.05) and favored JN. There was no difference in the improvement in pulmonary function between JN and UN therapy in children with an initial FEV1/FVC > 75% predicted but when FEV1/FVC < 75%, the improvement in FEV1 again favored the JN (UN+0.2 vs JN+0.47; p<0.05). CONCLUSION: For the treatment of acute exacerbations of asthma in children, there is no greater bronchodilator response when albuterol is administered by a UN than by a JN.

The Mexican asthma cure. Systemic steroids for gullible gringos.

Asthmatic patients from western Canada and the United States have reported that after visits to an asthma clinic in Mexicali, Mexico, they return home substantially improved or cured having received "a bronchodilator medication unavailable in the United States or Canada because of the big drug companies." Analysis of these medications reveals that the most commonly prescribed combination is the glucocorticoid triamcinolone (unscored white tablets) and the antihistamine chlorpheniramine (coated biconvex orange or red tablets). Occasionally benzodiazepines are added to these medications. The patients are assured that the medications which they have been given are free of side effects and specifically, that corticosteroids are not used. Such therapy is dangerous to the patient who not only is unaware of the medications that he or she is taking, but is unlikely to mention this therapy to his or her physician. These patients risk drug interactions, medication side effects, and the possibility of adrenal failure either with a stress to their system or on withdrawal of drug treatment. Patients are also at risk of abandoning safer forms of asthma therapy for the miracle cure. We, too, are partially responsible for these unethical practices by avoiding the use of steroids and undertreating our patients at times, leaving them unnecessarily restricted and eager for any form of relief.

Efficacy of recombinant human deoxyribonuclease I in the hospital management of respiratory syncytial virus bronchiolitis.

OBJECTIVE: To evaluate the effect of recombinant human deoxyribonuclease I (rhDNase) in shortening the length of the hospitalization and improving the chest radiographs (CXRs) in hospitalized infants with respiratory syncytial virus (RSV) infection as a result of its mucolytic properties. METHODS: Randomized, double-blind, placebo-controlled investigation of 75 patients with RSV bronchiolitis. The study was conducted at the University of Michigan Medical Center and St. Joseph Mercy Hospital, both in Ann Arbor, MI. RESULTS: The respiratory rate, wheezing, and retraction difference scores, obtained by subtracting the hospital discharge score from the corresponding hospital admission score, show no difference between the two groups, but the CXR difference scores show that the rhDNase group improved by 0.46 while the placebo group worsened by 0.60 (p < 0.001). Analysis of covariance for the hospital discharge CXR score after adjusting for the hospital admission score for both groups was done. There was a difference in scores between the two groups, with adjusted mean for the study group of 2.03, and 2.76 for the placebo group (p < 0.001). Paired t test statistics in each of the two groups were computed. For the placebo group, the mean increase of 0.60 was significant (p = 0.02), and the mean decrease of 0.46 for the rhDNase group was also significant (p = 0.02). A one-way analysis of covariance with the hospital discharge CXR scores as the dependent variable and the hospital admission score as the covariate showed that there was a significant difference between the groups (p = 0.01). CONCLUSION: In patients with RSV bronchiolitis, there was significant improvement in the CXRs with the use of rhDNase compared to significant worsening in the placebo group. To our knowledge, this is the first report of the use of rhDNase to treat RSV bronchiolitis.

Mucus-depleted frog palate as a model for the study of mucociliary clearance.

To better understand the frog palate model of mucociliary transport, we measured the transport rate of mucus (MTR) from the leopard frog, Rana pipiens, and from the bullfrog, R. catesbeiana, recorded the stability of the MTR over a period of hours and days and over the course of 1 yr, and measured the viscoelasticity, percent solid composition, and spinnability (filance) of mucus from both species. Bullfrog mucus was less rigid than leopard frog mucus (log G* at 1 rad/s 2.09 vs. 2.61; P less than 0.01) and had a higher viscosity-to-elasticity ratio (tan delta at 1 rad/s 0.36 vs. 0.26; P less than 0.05). It also had a lower solids content (8.71 vs. 13.72%; P = 0.02), and there was a trend to lower spinnability for bullfrog mucus (filance 26.7 vs. 33.5 mm). These data suggest that bullfrog mucus has viscoelastic properties similar to normal mammalian respiratory mucus and leopard frog mucus has viscoelasticity similar to sputum samples. MTR was significantly slower in the winter than in the summer months (17 vs. 30 mm/min; P less than 0.0001). Although the leopard frog palate could be used for at least 7 consecutive days without exhaustion, bullfrog palates could be used for only 5 days. Palates of either species could generally be tested for 6 h/day without a significant decrease in MTR. These data clarify some of the sources of variability in the use of this system and suggest methods of standardization.

Ring distraction technique for measuring surface tension of sputum: relationship to sputum clearability.

Poor sputum clearance has been related to sputum adhesion tension. In this study, we describe a modified du Noüy ring method for measuring the surface tension (gamma) of small samples of sputum and for comparinge the calculated work of adhesion (Wad) for sputum specimens with the measured mucociliary transportability (MCTR) and cough transportability (CTR). The gamma, as measured by this method, correlates with gamma measured by sputum contact angle on a low-surface-energy solid (R2 = 0.368, P = 0.03). There is a small but significant difference in measurements made by these two methods (P = 0.03). Wad calculated from the surface tension ring method is inversely correlated with CTR (R2 = 0.181, P = 0.004) but has no correlation with MCTR in this study. The miniaturized ring method gives accurate and reproducible measurements of the surface tension of small amounts of respiratory secretions. Because sputum behaves enough like a liquid that the assumptions made in using the Young equation to calculate Wad appear valid, we also showed that the Neumann equation can be used to determine the surface tension of sputum by its contact angle on tetrafluoroethylene (Teflon).

Neonatal capsaicin treatment alters basal pulmonary mechanics and response to methacholine in F344 rats.

Full methacholine dose-response curves were performed on anesthetized tracheostomized Fischer 344 adult rats treated neonatally with capsaicin (50 mg/kg) or with vehicle alone. Capsaicin, the hot extract of pepper, releases substance P (SP) from nonmyelinated sensory nerve endings and causes acute bronchoconstriction and airway microvascular leakiness. Chronic treatment with capsaicin leads to depletion of SP and other tachykinins from afferent C-fibers and can therefore be used as a tool to investigate the contribution of SP innervation to airway responses. The rats (9 controls and 6 treated with capsaicin) were paralyzed with succinylcholine and mechanically ventilated at a constant tidal volume and frequency. Airway resistance (RL) and dynamic compliance (Cdyn) were determined at each dose of methacholine from measurements of volume, flow, and transpulmonary pressure. Capsaicin-treated rats were found to have a significantly reduced baseline RL [0.150 +/- 0.039 (SD) vs. 0.225 +/- 0.050 cmH2O.ml-1.s, P = 0.009] and a correspondingly significantly elevated Cdyn (0.371 +/- 0.084 vs. 0.268 +/- 0.053 ml/cmH2O, P = 0.012). There was no significant difference in sensitivity to methacholine, but the maximal response to methacholine was significantly greater in the capsaicin-treated rats. In terms of RL, the maximal response for capsaicin-treated rats was 6.03 x baseline +/- 0.98 vs. 4.30 x baseline +/- 1.80 (P = 0.05) for controls, and for Cdyn changes the maximal decrease was 5.75 x baseline +/- 1.22 vs. 3.83 +/- 0.69 (P = 0.002). The observed differences in RL and Cdyn coupled with the differences in maximal responses can be attributed to the selective destruction of a subpopulation of pulmonary afferent C-fibers.(ABSTRACT TRUNCATED AT 250 WORDS)